During the next four years, I plan to continue my studies of the interactions between circulating granulocytes, the plasma complement system and the vascular endothelium. Based on our initial studies of the acute granulocytopenia of hemodialysis and nylon fiber filtration leukapheresis, we have shown that, in both man and animals, intravascular complement activation (and the concomitant generation of C5a des arg) leads to augmented granulocyte adhesiveness and auto-aggregation. Peripheral granulocytopenia results from embolization of these aggregates to the capillary bed and their temporary sequestration therein, and the stimulated granulocytes produce local endothelial damage manifest initially by the development of interstitial edema and later by end organ dysfunction. My plan is to explore the multiple ramifications of this novel, and likely very important, chain of biological events (in vitro, in animals, and in patients). Briefly, I plan to define the cellular mechanisms whereby (1) C5a des arg induces granulocyte adhesiveness and auto-aggregation, and (2) how the stimulated cells induce disruption of endothelial monolayers. I hope to define the clinical relevance of this granulocyte sequestration as a mechanism for (3) the otherwise-unexplained granulocytopenia and (4) the vascultis associated with disseminated intravascular complement activation (bacterial sepsis, major trauma, severe burns, endotoxinemia, pancreatitis and myocardial infarction). I plan to develop (5) our method of granulocyte aggregometry as a technique for evaluating granulocyte plasma membrane function and as an assay system for the detection of circulating C5a des arg in patients with intravascular complement activation. As is hopefully evident from our published data, the majority of the studies I propose can and will be performed in my laboratory, but, in addition, I have been sufficiently fortunate to enlist the support of three important collaborators (all of whom have worked with me in the past)--Dr. White will provide expert ultrastructural data, Dr. Dalmasso will help with advanced complement biochemistry, and Dr. Brigham will provide his sheep model which is so eminently suitable for the study of endothelial damage and end organ dysfunction in vivo. Throughout the studies primary emphasis will be placed upon definition of basic mechanisms, determination of clinical relevance and pharmacol (Text Truncated - Exceeds Capacity)